This K24 is submitted on behalf of a PI with a strong commitment to a career in patient-oriented research and mentoring junior faculty; the award will serve to enhance a large interdisciplinary effort in which the PI plays a central role. The project cuts across traditional specialty and sub-specialty lines in the study of cerebral AVMs. This disease serves as a model for understanding several aspects of general cerebrovascular physiology and adaptive mechanisms that are likely to be important in the management of stroke syndromes. Columbia-Presbyterian Medical Center has widely recognized, well-established patient-oriented research and training programs related to the clinical neurosciences and includes a high-quality research environment with staff capable of productive collaboration with the PI. The parallel specific aims of the project focus on (a) the affect of AVM shunt flow on functionally intact adjacent brain tissue (Specific Aim I) and (b) the effects of altered cerebral hemodynamics (as determined by clinical, physiologic and morphologic data) on the natural history of the disease (Specific Aim II). Aim I, which corresponds in part to work funded by NS27713, involves the hypothesis that NO-ergic mechanisms are responsible for adaptation to chronic decrease in perfusion pressure. Antagonists and agonists will be used to manipulate cerebral perfusion. Aim II addresses the association of cerebral hemodynamics with the occurrence of spontaneous intra cerebral hemorrhage during the natural course of the disease and is primarily funded by NS34949. We hypothesize that a discrete set of risk factors can be used to predict the natural history of spontaneous AVM hemorrhage; stratification algorithms for clinical trials will be the direct result. The immediate goals of the PI are to continue development of a multi-disciplinary effort to study the pathophysiology and natural history of cerebral AVMs. In concert with the PI's collaborators, long-term goals include the development, organization and performance of clinical trials to assess treatment efficacy. Further, a patient-oriented clinical research program in cerebrovascular disease will be developed that is linked to parallel investigations of the basic pathobiology of cerebral vascular malformations and computational modeling of the cerebral circulation. The K24 career development award will be an important means of maintaining the high productivity of the PI and the AVM research project and will provide great potential to mentor and maintain junior faculty in patient-oriented research careers in the pathophysiology of clinical cerebrovascular disease.